DESCRIPTION: The overall goal of this application is to elucidate mechanisms of growth regulation to understand the processes that lead to proliferative disorders. Growth factors have been demonstrated to control growth through their actions on G1 cell cycle specific proteins which, in turn, control the actions of tumor suppressor genes. It is imperative to understand the regulation of D-type cyclin activities and their effects on specific growth suppressive pathways. This objective will be accomplished through the following specific aims: Aim 1 will determine the substrate specificity of each cyclin D/cdk4 complex towards Rb family member proteins. Aim 2 will determine the mechanism of ternary cyclin D/cdk4/p27kip1 or cyclin D/cdk4/p21cip1 complex formation and the dynamics of addition of newly synthesized subunits to, and concomitant loss of, old subunits from such complexes, and how such alterations modulate cdk activity and substrate specificity. Aim 3 will determine the mechanism of activation of cdk4 activation, i.e. identify the steps required to generate catalytically active enzyme in vivo after complex formation with a cyclin D partner. Aim 4 will identify the regions of each D-type cyclin responsible for its interaction with cdk4.